CN114699398A - Inhibitor for treating renal clear cell carcinoma - Google Patents
Inhibitor for treating renal clear cell carcinoma Download PDFInfo
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- CN114699398A CN114699398A CN202210450599.3A CN202210450599A CN114699398A CN 114699398 A CN114699398 A CN 114699398A CN 202210450599 A CN202210450599 A CN 202210450599A CN 114699398 A CN114699398 A CN 114699398A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention discloses an inhibitor for treating renal clear cell carcinoma, and the research results of the applicant show that L-methionine sulfoxide imide (MSO), hereinafter referred to as MSO, is used as a retarder of glutamine synthetase GLUL (glutamine-ammonia ligand), has the functions of obviously inhibiting the growth, proliferation and metastasis of renal clear cell carcinoma, and brings new hope for treating the renal clear cell carcinoma; furthermore, the L-methionine sulfoxide imide and everolimus can effectively inhibit the growth and proliferation of renal clear cell carcinoma in an animal level, and the combined use has more excellent inhibition function on the growth and proliferation of the renal clear cell carcinoma, so that the L-methionine sulfoxide imide and everolimus combined type renal clear cell carcinoma has great potential for treating the renal clear cell carcinoma.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of L-methionine sulfoxide imide as a medicine for treating renal clear cell carcinoma.
Background
Clear cell renal cell carcinoma (ccRCC) is the most common type of pathology for renal cell carcinoma (70% -75%). Research shows that VHL (VHL Hippel-Lindau) gene function inactivation is an important molecular basis for the generation and development of the ccRCC, wherein VHL abnormality such as mutation, methylation and the like exists in more than 90% of the ccRCCs. The greatest progress in renal cancer drug therapy over the past decades has been drugs that target the VEGFR (vascular endothelial growth factor receptor) downstream of the VHL-HIF (hypoxia inducible factor) pathway, such as sunitinib, sorafenib, and the like. These anti-angiogenic drugs do achieve a certain therapeutic effect in some metastatic renal cancers; however, these drugs often have off-target effects and irritating toxic side effects. Recent studies suggest that targeting the VHL-HIF pathway leading to metabolic reprogramming may be a potential therapeutic strategy for ccRCC. Overactivation of the VHL-HIF pathway results in renal cancer cells always being in a pseudo-hypoxic environment, with intermediary metabolites of the TCA cycle in ccRCC based on the Warburg effect being more derived from the "anaplerosis" of glutamine, and thus being more dependent on glutamine compared to other tumors. Previous research also finds that glutamine depletion (glutamine depletion) can cause the growth of the ccRCC cells to be obviously inhibited and increase the apoptosis of the cells; in vivo and in vitro studies also show that inhibitors of GLS (glutaminase) can also achieve the same effect as glutamine deprivation in ccRCC, leading to significant anti-tumor proliferative effects. Therefore, glutamine plays an important role in the occurrence and development of kidney cancer as an important 'energy source', and the targeted reprogramming of glutamine metabolism is expected to become a new direction for treating kidney cancer.
L-methionine sulfoximine is a specific inhibitor of the glutamine synthetase GLUL (glutamate-ammonium ligand). GLUL is a key enzyme for de novo synthesis of glutamine, catalyzes glutamic acid and ammonia to be converted into glutamine under the dependence of ATP (adenosine triphosphate) enzyme, and further participates in the metabolic function of a glutamine pool, promotes the synthesis of nucleotide, lipid and the like; on the other hand, the toxicity of intracellular ammonia is relieved. The abnormal expression of GLUL is closely related to the occurrence of various tumors in the past research. To date, there is no literature reporting the role of GLUL and its blocking agent L-Methionine Sulfoximine (MSO) in renal clear cell carcinoma.
Everolimus (EVE) is an mTOR inhibitor, mTOR is an important serine-threonine kinase, the activity of the mTOR inhibitor is up-regulated in various tumors, and the prior research reports that the mTOR activation in kidney cancer is obviously enhanced. Everolimus inhibits the activity of the mTOR pathway by binding to the intracellular protein FKBP12 to form the inhibitory complex mTORC 1. Inhibition of mTOR pathway activity may lead to down-regulation of phosphorylation and reduced activity of the transcriptional regulator S6 ribosomal protein kinase (S6K1) and the eukaryotic elongation factor 4E-binding protein (4E-BP), thereby interfering with translation and synthesis of cell cycle, glycolysis, and other related proteins. Furthermore, everolimus also inhibits the neogenesis of blood vessels by down-regulating the expression of Vascular Endothelial Growth Factor (VEGF), and also inhibits the growth and proliferation of a variety of cells such as tumor cells, endothelial cells, fibroblasts, vascular smooth muscle cells, and the like. Currently, everolimus has been used clinically as a second line treatment for patients with advanced renal cell carcinoma after failure of sunitinib or sorafenib treatment. But the treatment effect is still not good enough at present, and the combination of other medicines to enhance the effect of everolimus has important clinical significance.
Disclosure of Invention
The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, the invention mainly aims to provide the application of the L-methionine sulfoxide imide in renal clear cell carcinoma, and experiments prove that the L-methionine sulfoxide imide can effectively inhibit the proliferation and metastasis of the renal clear cell carcinoma.
The purpose of the invention is realized by the following technical scheme:
use of L-methionine sulfoximine in a medicament for inhibiting the growth, proliferation and metastasis of renal clear cell carcinoma.
Preferably, wherein the renal clear cell carcinoma is caused by 786-O cells.
Preferably, the L-methionine sulfoximine is used at a concentration of 30 mmol/L.
Preferably, wherein the route of administration of the medicament is intraperitoneal injection.
The L-methionine sulfoxide imide is combined with everolimus to be applied to the medicine for inhibiting the growth, proliferation and metastasis of renal clear cell carcinoma.
Preferably, wherein the renal clear cell carcinoma is caused by 786-O cells.
Preferably, the dosage of the L-methionine sulfoxide imide is 10mg/kg, and the dosage of the everolimus is 2.5 mg/kg.
Preferably, the administration route of the L-methionine sulfoxide imide is intraperitoneal injection, and the administration route of the everolimus is oral administration.
Compared with the prior art, the invention has at least the following advantages:
the application of the L-methionine sulfoxide imide in renal clear cell carcinoma provided by the invention has the functions of obviously inhibiting the growth, proliferation and metastasis of renal clear cell carcinoma by taking the L-methionine sulfoxide imide as a retardant of GLUL and inhibiting the heavy end synthesis of glutamine. The application expands the application range of the L-methionine sulfoxide imide, improves the application value of the L-methionine sulfoxide imide, brings new hope for the treatment or health care of renal clear cell carcinoma, and improves the activity or reduces the side effect by using the L-methionine sulfoxide imide as a lead compound through structural modification or modification, and is also helpful for further developing new medicines for resisting the renal clear cell carcinoma. In addition, the combination of L-methionine sulfoxide imide and everolimus has better curative effect on metastatic renal clear cell carcinoma.
Drawings
In order to more clearly illustrate the embodiments of the present invention, reference will now be made briefly to the embodiments or to the accompanying drawings that are needed in the description of the prior art.
FIG. 1 shows that GLUL is highly expressed in renal clear cell carcinoma and is closely related to the pathological stage and prognosis of tumors. Wherein A is GLUL protein comparison of paracancerous and tumoral in renal clear cell carcinoma patient specimens from the public database CPTAC; b is the Copy Number Variation (CNV) of GLUL in public databases and the prognosis relation of renal clear cell carcinoma; c is the result of immunohistochemical detection of GLUL expression in renal clear cell patient chip, D and E are the results of the relationship between GLUL expression level and grade and prognosis, respectively;
FIG. 2 shows that L-Methionine Sulfoximine (MSO) can inhibit the growth and proliferation of renal clear cell carcinoma cell lines at the cellular and organoid levels in vitro. Wherein A is the result of CCK8 experiment after MSO with the concentration of 30mM treats the renal clear cell carcinoma 786-O cell, B is the result of clone formation experiment after MSO with the concentration of 30mM treats the renal clear cell carcinoma 786-O cell, and C is the result of tumor formation experiment after MSO with the concentration of 30mM treats the renal clear cell carcinoma organoid;
FIG. 3 shows that L-Methionine Sulfoximine (MSO) has the function of inhibiting the growth and proliferation of renal clear cell carcinoma while increasing the pharmaceutical effect of everolimus on a model of subcutaneous 786-O cell transplantable tumor. Wherein A and B are schematic diagrams of tumor mass and tumor volume of mouse subcutaneous neoplasia, C and D are comparison of volume and tumor weight of subcutaneous transplanted tumor;
FIG. 4 shows that L-Methionine Sulfoximine (MSO) has the function of inhibiting the growth and proliferation of renal clear cell carcinoma in PDX model, and simultaneously increases the pharmaceutical effect of everolimus. Wherein A and B are the results and the volume schematic diagram of PDX treated by MSO combined with everolimus, and C and D are the volume and weight comparison of the subcutaneous transplanted tumor treated by MSO combined with everolimus.
Detailed Description
The present invention will be further described with reference to the following drawings and examples, which are illustrative only and not intended to be limiting, and the scope of the present invention is not limited thereby.
In the application of the L-methionine sulfoxide imide provided by the invention in renal clear cell carcinoma, the raw materials and reagents can be purchased from the market, wherein the molecular formula of the L-methionine sulfoxide imide is as follows: CH3S (O) (═ NH) CH2CH (NH2) CO2H, molecular weight 180.23, molecular structural formula:
the invention is further illustrated by the following examples:
example 1: GLUL is highly expressed in renal clear cell carcinoma (ccRCC), and is closely related to the prognosis of renal clear cell carcinoma.
We analyzed GLUL protein expression level and copy number changes in ccRCC and paracarcinoma tissues using TCGA public database resources to understand the important role of GLUL expression in ccRCC. Meanwhile, the relation between GLUL and the fuhrman classification and prognosis of ccRCC is analyzed by using a ccRCC tissue chip and a follow-up database of the unit (China civil liberation army special medical center).
We analyzed the ccRCC proteomics public database of Clinical proteomics Tumor Analysis association (CPTAC), found that the expression level of GLUL in the primary foci of ccRCC is significantly higher than that of the paracancer tissues, suggesting that GLUL is associated with ccRCC development [ fig. 1A ]. We analyzed the ccRCC database in TCGA using UCSC Xena (https:// Xena. UCSC. edu) and found that high copy number of GLUL correlates with poorer clinical prognosis of ccRCC [ FIG. 1B ]. Furthermore, we found, using the central ccRCC tissue chip line IHC, that the expression level of GLUL positively correlated with the fuhrman rating of ccRCC [ fig. 1C-1D ], and combined with the follow-up database, that the prognosis for high expression of GLUL (H-score > 4) was worse [ fig. 1E ].
Example 2: L-Methionine Sulfoximine (MSO) can inhibit the growth and proliferation of renal clear cell carcinoma cell lines at the cellular and organoid levels in vitro.
The growth and proliferation capacity of the cells and organoids after MSO treatment were tested by CCK8, clonogenic and organoid assays.
For the CCK8 experiment: 786-O cells were digested with 0.25% trypsin, the appropriate number of cells counted, resuspended in complete medium, and then 0.1X 104Adding into 96-well plate, culturing for 4 hr with CCK8 until the next day cell is completely attached to the wall, and measuring absorbance at 450nm wavelength to obtain absorbance value of day 0. Dividing into two groups (control group DMSO 1 ‰, MSO group MSO 30mM), each group having 5 multiple wells, adding corresponding culture medium, culturing, and testing aspiration continuously for 4 daysAnd (4) luminosity. It was seen that 30mM had a significant growth inhibitory effect on the 786-O cell line (FIG. 2A).
For clone formation experiments, 786-O cells were counted and 0.1X 10 cells were taken4Six-well plates were plated per well, and the plates were divided into control group (DMSO 1 ‰) and MSO group (MSO 30mM) and cultured for 14 days, and then stained for cells were collected. After washing with PBS 3 times, fixing paraformaldehyde and methanol for 10 minutes respectively, washing with PBS 3 times, dyeing with crystal violet for 2 minutes, drying and collecting the picture. The results show that MSO has a significant inhibitory effect on the growth of the 786-O cell line (FIG. 2B).
For a 3D organoid culture experiment, a 3D organoid culture model is established by using a fresh tumor tissue specimen of a ccRCC patient, and the tumor specimen of the patient is cut into tissue fragments with the size of 1-2mm after fat and necrotic tissues are removed; the cells were digested with collagenase type II at 37 ℃ for 2 hours and the cell suspension was passed through a 40 μm sieve. 350g, centrifuging for 5 minutes at 4 ℃, and keeping cell precipitation; laying 1 layer of Matrigel (matrix) in the middle of a 24-hole plate and curing the matrix; use Matrigel and medium according to 1 x 104Diluting the cells at a concentration of 40. mu.l/well, spreading the cell suspension on a bottom Matrigel gel, and adding 500ml of culture medium to each well after the cell suspension is solidified; after 7 days of growth, 3D organoids were divided into two groups (control group DMSO 1 ‰, MSO group MSO 30mM), and pictures were taken after 7 days. It can be seen that 30mM had a significant growth and clonogenic inhibitory effect on the ccRCC 3D organoids (FIG. 2C).
Example 3: l-methionine sulfoxide imide (MSO) has effects of inhibiting growth and proliferation of renal clear cell carcinoma in subcutaneous inoculation and PDX model, and increasing everolimus drug effect
The growth and proliferation effects of MSO on ccRCC and the anti-tumor effect of combined everolimus are detected by using a subcutaneous inoculation 786-O cell line and a PDX model.
For the subcutaneous graft tumor experiments, after expansion of the 786-O cell line, PBS: matrigel 1: 1 ratio of resuspended cells, cell concentration 5 x 106100 μ l. Selecting 4-week-old nude mice, injecting 100 μ l cell suspension subcutaneously into one side of the nude mice back, and allowing the tumor volume to reach 50-100mm3Medication is given. Four groups (no significant difference in initial tumor volumes in the four groups) were designed as controls (DMS)O1 ‰, gavage), MSO group (10mg/kg, i.p.), Everolimus group (2.5mg/kg, gavage), and combination of two drugs group (MSO 10mg/kg, Everolimus 2.5 mg/kg). Tumor size was recorded 2 times per week and nude mice were sacrificed when the maximum tumor size was about 1.0 cm. Tumor size and weight were measured and tumor volume was calculated by the formula volume length width 2. The experimental results suggest that MSO and Everolimus both have tumor inhibition effect, and the two drugs can more significantly inhibit tumor growth when used together (fig. 3A-D). As can be seen from FIGS. 3A-D, the tumor size and mass of the nude mice without DMSO was greatly reduced by 65-70% or more compared to the nude mice with MSO or EVE alone, while the tumor size and mass of the nude mice with the combination of MSO + EVE was further reduced by 75-85% compared to the nude mice with MSO or EVE alone.
For PDX experiments, tumor tissues of ccRCC patients were removed and minced into tissue pieces of 1-2mm in size. After isoflurane inhalation anesthesia was effected, the NPG mice were taken in the prone position and the dorsal rib area was dehaired. The kidney was then extruded through an incision that was approximately 1cm in the area of the spinal costal region, with fascia and muscle isolated layer by layer. The kidney capsule was gently lifted with forceps, an incision of about 2mm in length was made with an ophthalmic scissors, and the minced tumor tissue piece was placed under the kidney capsule. The kidney was returned to the posterior abdominal cavity and the incision was closed layer by layer. Weekly manipulations palpate the renal area and assess the growth of the transplants. NPG mice are sacrificed when the maximum diameter of the transplanted tumor is about 6-8mm, the amplified tumor tissue is cut into tissue blocks with the size of about 2mm, and the tissue blocks are inoculated under the skin of the back of one side of the NPG mice. Tumor size was measured twice a week when tumor volume reached about 200mm3Medication is given. The experiment was divided into four groups (four groups with no significant difference in initial tumor volume) including a control group (DMSO 1 ‰, intragastric), an MSO group (10mg/kg, i.p.), an Everolimus group (2.5mg/kg, intragastric) and a two-drug combination group (MSO 10mg/kg, Everolimus 2.5 mg/kg). NPG mice were sacrificed when the tumor maximum diameter was about 1.5 cm. Tumor size and weight were measured and tumor volume was calculated by the formula volume length width 2. The experimental results suggest that MSO and Everolimus both have tumor inhibition effect, and the combination of the two drugs can more significantly inhibit tumor growth (FIGS. 4A-D). As can be seen from FIGS. 4A-D, the tumor size and mass of the non-NPG mice were greatly reduced by 50-60% or more compared with those of the MSO or EVE alone, while those of the MSO + EVE combination mice were further reduced by 30-50% compared with those of the MSO or EVE alone.
The application of the L-methionine sulfoxide amide in renal clear cell carcinoma provided by the application firstly provides the function of glutamine synthetase GLUL (glutamine-ammonia lipid) inhibitor MSO (methionine sulfoxide, L-methionine sulfoxide imide) for treating renal clear cell carcinoma, brings new hope for treating renal clear cell carcinoma, is also favorable for further developing new medicaments or health products, and is expected to further improve the activity or reduce side effects by using the L-methionine sulfoxide imide as a lead compound through structural modification or transformation.
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; such modifications and substitutions do not depart from the spirit and scope of the present invention, and they should be construed as being included in the following claims and description.
Claims (8)
- Use of L-methionine sulfoximine in a medicament for inhibiting the growth, proliferation and metastasis of renal clear cell carcinoma.
- 2. The use of claim 1, wherein the renal clear cell carcinoma is caused by 786-O cells.
- 3. The use according to claim 1, wherein the L-methionine sulfoximine is used at a concentration of 30 mmol/L.
- 4. The use of claim 1, wherein the route of administration of the medicament is intraperitoneal injection.
- Use of L-methionine sulfoximine in combination with everolimus in a medicament for inhibiting the growth, proliferation and metastasis of renal clear cell carcinoma.
- 6. The use of claim 5, wherein the renal clear cell carcinoma is caused by 786-O cells.
- 7. The use according to claim 5, wherein the L-methionine sulfoximine is administered at a dose of 10mg/kg and the everolimus is administered at a dose of 2.5 mg/kg.
- 8. The use of claim 5, wherein the route of administration of L-methionine sulfoximine is intraperitoneal injection and the route of administration of everolimus is oral.
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Citations (3)
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|---|---|---|---|---|
| US20120230989A1 (en) * | 2009-11-10 | 2012-09-13 | Mayo Foundation For Medical Education And Research | Methods and materials for treating renal cell carcinoma |
| CN107027291A (en) * | 2014-06-13 | 2017-08-08 | 卡利泰拉生物科技公司 | With the combination treatment of glutamine enzyme inhibitor |
| CN113846047A (en) * | 2021-06-22 | 2021-12-28 | 姜海涛 | Kidney targeting drug-loaded exosome and application and drug for treating kidney diseases |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120230989A1 (en) * | 2009-11-10 | 2012-09-13 | Mayo Foundation For Medical Education And Research | Methods and materials for treating renal cell carcinoma |
| CN107027291A (en) * | 2014-06-13 | 2017-08-08 | 卡利泰拉生物科技公司 | With the combination treatment of glutamine enzyme inhibitor |
| CN113846047A (en) * | 2021-06-22 | 2021-12-28 | 姜海涛 | Kidney targeting drug-loaded exosome and application and drug for treating kidney diseases |
Non-Patent Citations (1)
| Title |
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| 黄义强: "组蛋白去甲基化酶PHF8上调GLUL促进肾透明细胞癌脂质沉积的研究", 中国博士学位论文全文数据库 医药卫生科技辑, no. 01, 15 January 2022 (2022-01-15), pages 067 - 11 * |
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